MXPA03000367A

MXPA03000367A - 4-phenyl-pyridine derivatives as neurokinin-1 receptor antagonists.

Info

Publication number: MXPA03000367A
Application number: MXPA03000367A
Authority: MX
Inventors: Heinz Stadler
Original assignee: Hoffmann La Roche
Priority date: 2000-07-24
Filing date: 2001-07-20
Publication date: 2003-05-27
Also published as: NZ523452A; YU2803A; CY1106113T1; ZA200300219B; NO20030353D0; ECSP034446A; US20020038030A1; GT200100148A; DE60118569D1; US6624176B2; US6576762B2; HK1058360A1; PA8522801A1; TWI287003B; HU229231B1; PE20020258A1; HUP0301272A2; KR20030015898A; CN1192032C; UY26851A1

Abstract

The invention relates to compounds of general formulas (IA) or (IB) wherein R1 is (a), (b), (c), (d) or is -NH(CH2)2OH, -NR3C(O)CH3 or -NR3C(O)-cyclopropyl; R2 is methyl or chloro; R3 is hydrogen or methyl; R is hydrogen or -(CH2)2OH; and n is 1 or 2 and pharmaceutically acceptable acid addition salts thereof. These compounds have a good affinity of the NK-1 receptor and therefore they may be used in the treatment or prevention of diseases, related to this receptor.

Description

DERIVATIVES OF 4-PHENYL-PYRIDINE AS ANTAGONISTS OF THE NEUROQUININE RECEPTOR-l DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formulas where R1 is or is -NH (CH2) 2OH, -NR3C (0) CH3 or -NR3C (0) -cyclopropyl; R2 is methyl or chloro; R3 is hydrogen or methyl; R is hydrogen or - (CH2) 2? H; and n is 1 or 2 and its pharmaceutically acceptable acid addition salts. REF. 144492 Compounds similar to those described in the present application have been described in EP 1035115. The compounds of the formulas IA and IB and their salts are characterized by valuable therapeutic properties. It has surprisingly been found that the compounds of the present invention are antagonists of the Neurokinin 1 receptor (NK-1, substance P). Substance P is a undecapeptide that is found in the natural state belonging to the tachykinin family of peptides, the latter being called because of its early contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of protein G-coupled receptors. The neuropeptide receptor for substance P (NK-1) is widely distributed through the nervous system of mammals (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a series of diverse biological processes. The central and peripheral activities of the tachykinin substance P of mammals has been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma and inflammatory bowel disease as well as mediation of emetic reflex and modulation of central nervous system (CN?) Disorders. such as Parkinson's disease (Naurosci, Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645) . Evidence for the usefulness of tachykinin receptor antagonists in pain, migraine, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, edema, such as edema caused by thermal injury, chronic inflammatory diseases such as arthritis rheumatoid, asthmatic / bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory bowel diseases including ulcerative colitis and Crohn's disease, eye injury and ocular inflammatory diseases reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93, 1993. In addition, Neurokinin 1 receptor antagonists are developed for the treatment of a series of physiological disorders associated with an excess of tachykinin imbalance, in particular substance P. Examples of states where Substance P involved include central nervous system disorders such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798). Neurokinin-1 receptor antagonists are They are also used for the treatment of motion sickness and for the treatment of induced vomiting. In addition, in The New England Journal of Medicine, Vol. 340, no. 3 190-195, 1999 the reduction of emesis induced by cisplatin by a selective neurokinin-1 receptor antagonist has been described. In addition, US 5,972,938 describes a method for the treatment of psychoimmunological or psychosomatic disorders by administration of a tachykinin receptor, such as NK-1 receptor antagonist. The utility of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in "Neuropeptides, 32 (1), 1-49, (1998)" and "Eur. J. Pharmacol., 383 (3). ), 297-303, (1999). " The compounds of formulas IA and IB can also be used in the form of their prodrugs. Examples are esters, N-oxides, phosphate esters, glycoamide esters, conjugated glycerides and the like. The prodrugs can add to the value of the present compounds advantages in adsorption, pharmacokinetics in distribution and transport to the brain. Objects of the present invention are the compounds of formulas IA and IB and their pharmaceutically acceptable salts, the preparation of the aforementioned compounds, medicaments containing them and their preparation as well as the use of the aforementioned compounds in the control or prevention of diseases, especially of diseases and disorders of the type referred to above or in the preparation of corresponding medicaments. The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders or emesis by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as a period of at least two weeks during which, most of the day and almost every day, there is depressive mood or loss of interest or pleasure in all or almost all activities. Preferred examples are compounds of the formula IA, wherein R 2 is methyl, for example the following compounds: N- (3, 5-bis-trifluoromethyl-benzyl) -N-methyl-4-o-tolyl-6- [1, 2,4] triazol-1-yl-nicotinamide, N- (3, 5-bis-trifluoromethyl-benzyl) -6- (2-hydroxy-ethylamino) -N-methyl-4-o-toli1-nicotinamide, (3 4-hydroxy-4'-o-tolyl-3,, 5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methyl-amide, (3, 5-bis-trifluoromethyl-benzyl) -methyl-amide of 4- (2-hydroxy? -ethoxy) -4'-o-tolyl-3, 4,5,6-tetrahydro-2H- [1, 2 '] b? P? Ridinyl-5'-carboxylic or (R) -N- (3,5-bis-trifluoromethyl-benzyl) -6- (3-hydroxy-pyrrolidin-1-yl) -N- methyl-4-o-tolyl-nicotinamide. Also preferred are compounds of formula IA, wherein R2 is chloro. An example of this compound is: (3, 5-b? S-tpfluoromethyl-benzyl) -methyl-amide of 4 '- (2-chloro-phen?) -4-hydroxy-3, 4, 5, 6 -tetrahydro-2H- [1,2 '] b? pyridinyl-5'-carboxylic acid. Preferred examples are compounds of formula IB, wherein R2 is methyl, for example the following compounds: 2- (3,5-b? S-tpfluoromethyl-phenyl) -N- [6- (2-hydroxy-ethylamino) -4 -otolyl-pir? dm-3-yl] -N-methyl-isobutyramide, 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2,3-dihydro- [1,4] oxazin -4-yl) -4-o-tol? L-pyridin-3-yl] -N-methyl isobutyramide, N- (6-acet? Lammo-4-o-tol? L-pyridin-3-yl) - 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide, N- [6- (acetyl-methyl-amino) -4-o-tolyl-pyridin-3-yl] -2- (3, 5-b? S-trifluoromethyl-phenyl) -N-methyl-isobutyramide, (5- { [2- (3,5-bis-trifluoromet? L-phenyl) -2-methyl-propionyl] - 3-o-tolyl-pyridin-2-yl) -amide of the cyclopropanecarboxylic acid, (5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4- or -tolyl-pyridin-2-yl) -methyl- cyclopropanecarboxylic acid amide or 2- (3,5-bis-trifluoromethyl-phenyl) -N- (6-imidazol-1-yl-4-o-tolyl-pyridin-3-yl) -N-methyl-isobutyramide. Also preferred are compounds of formula IB, wherein R2 is chloro, for example the following compound: 2- (3,5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- ( 2-hydroxy-ethylamino) -pyridin-3-yl] -N-methyl-isobutyramide. The present compounds of formulas IA and IB and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, with procedures described below, which process comprises a) reacting a compound of formula with a compound of formula to a compound of the formula wherein R1 and R2 have the meaning indicated above, b) reacting a compound of formula with a compound of formula V to give a compound of formula IA wherein R1 and R2 have the meaning indicated above, c) reacting a compound of formula with a compound of formula to a compound of formula wherein Z is Cl, Br, I, -OS (O) 2C6H4CH3 or -OS (0) 2CH3 and the other definitions of the substituents have been given above, or reacting a compound of formula with a compound of formula RSH XIV to a compound of the formulas wherein the definition of substituents has been given above, and if desired, converting the obtained compound to a pharmaceutically acceptable acid addition salt. According to variant a) of the process, DIPEA (N-ethyldiisopropyl-amine) is added to a mixture of a compound of formula II and a compound of formula III in dichloromethane and the mixture is stirred at temperatures between 35.degree. 40 ° C. The desired compound of formula IB is isolated after purification in good yields. Variant b) of the process describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula IA. The reaction is carried out in conventional manner, for example in a solvent, such as a mixture of toluene and triethylamine. The mixture is refluxed for about 1 hour. Variant c) of the process describes the reaction of a compound of formula VI with a compound of formula VIII to a compound of formula IA. This reaction is carried out by deprotonation of a compound of formula VI with KHMDS (potassium hexamethyldisilazide) and subsequent addition of a compound of formula VII. An appropriate solvent is tetrahydrofuran. The reaction is carried out at room temperature. Another method for the preparation of a compound of formula IA or IB is described in variant d) of the process. A compound of the formulas VIII or IX is treated with a compound of the formula XIV, which is, for example, 1, 2, 4-triazole, ethanolamine, 4-hydroxypiperidine, (R) -3-pyrrolidinol or morpholine. The reaction is carried out in THF, usually at 80-140 ° C. The salt formation is carried out at room temperature according to methods that are in themselves known and that are familiar to any person skilled in the art. They come into consideration not only salts with inorganic acids, but also salts with organic acids.

Examples of these salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methansulfonates, p-toluenesulfonates and the like. The reaction schemes that follow 1-3 describe the processes for the preparation of compounds of formulas IA and IB in more detail. The starting materials are known compounds or can be prepared according to methods known in the art. The following abbreviations have been used in the reaction schemes: PivCl pivaloyl chloride THF tetrahydrofuran TMEDA N, N, N ', N' -tetramethylethylene diamine DIPEA N-ethyldiisopropyl-amine KHMDS hexamethyldisilazide potassium Reaction scheme 1 definition of the substituents has been described above Reaction scheme 2 IA The substitution of the substituents is described above Reaction scheme 3 IB The definition of substituents has been described above. As indicated above, the compounds of the formulas IA and IB and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the neurokinin 1 receptor (NK-1, substance P). The compounds were investigated in accordance with the tests offered below. The affinity of the test compounds for the NKi receptor was evaluated at NKi receptors in CHO cells infected with the NK: human receptor (using the Semliki virus expression system) and radiolabelled with [3H] substance P (final concentration 0.6 nM). Binding assays were carried out in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 μg / ml), MnCl2 (3 mM) and phosphoramidon (2 μM). The binding assays consisted of 250 μl of membrane suspension (1.25xl05 cells / test tube), 0.125 μl of displacement agent buffer and 125 μl of [3H] substance P. The displacement curves were determined with minus seven concentrations of the compound. The test tubes were incubated for 60 minutes at room temperature after which time the contents of the tubes were filtered rapidly under vacuum through GF / C filters previously soaked for 60 minutes with PEI (0.3%) with 2 washes of 2 ml of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation. All assays were carried out in triplicate in at least 2 separate experiments. The affinity of the NK-1 receptor, given as pKi, is in the range between 8.40 - 9.24 for the described compounds.

The compounds of formulas IA and IB, as well as their pharmaceutically usable acid addition salts can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, the administration can also be carried out rectally, for example in the form of suppositories, or parenterally / for example in the form of injection solutions. The compounds of formula IA and IB and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert inorganic or organic excipients, for the production of tablets, coated tablets, dragees and hard gelatine capsules. Such excipients as lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, solid and liquid polyols, etc. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc. In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts to vary the osmotic pressure, buffers, masking agents or antioxidants. They may also still contain other therapeutically valuable substances. The dose can vary within wide limits and will obviously conform to the individual requirements of each particular case. In general, the effective dose for oral or parenteral administration is between 0.01 - 20 mg / kg / day, with a dose of 0.1 - 10 mg / kg / day being preferred for all the indications described. The daily dose for a human adult with a weight of 70 kg is therefore between 0.7-1400 mg per day, preferably between 7 and 700 mg per day. The following examples illustrate the present invention without limiting it. All temperatures are offered in degrees Celsius.

Example "N- (3, 5-bis-trifluoromethyl-benzyl) -N-methyl-4-o-tolyl-6- [1,2,4] triazol-1-yl-nicotinamide a) 6-chloro-N-methyl-nicotinamide To 50 g (317 mmol) of 2-chloronicotinic acid was added 230 ml (3.16 mol) of thionyl chloride at 0 ° C. After heating the mixture to reflux for 2 hours The excess thionyl chloride is removed by distillation. The brownish oily residue was dissolved in 250 ml of dichloromethane. The solution was treated with methylamine gas at 0 ° C until the exothermic reaction was no longer observed. The resulting suspension was diluted with 1000 ml of dichloromethane / water. The phases were separated and the aqueous phase was extracted with three 300 ml portions of dichloromethane. Drying of the organic phase with sodium sulfate and concentration gave 53.2 g (98%) of the title compound as a light yellow solid. MS m / e (%): 171 (M + H +, 15). b) 6-chloro-N-methyl-4-o-tolyl-nicotinamide To a solution of 3.41 g (20.0 mmol) of 6-chloro-N-methyl-nicotinamide in 80 ml of tetrahydrofuran was added dropwise at 0 ° C. 50 ml (50 mmol) of a 1 M solution of o-tolyl magnesium chloride in tetrahydrofuran. After the addition was complete, it was allowed to warm to room temperature and was stirred for 1.5 hours. The mixture was again cooled to 0 ° C, followed by the dropwise addition of 5.7 ml (100 mmol) of acetic acid and a solution of 5.1 g (22 mmol) of 2,3-dichloro-5,6-dicyano- 1, 4-benzoquinone in 18 ml of tetrahydrofuran. After the addition was complete, it was allowed to warm to room temperature and was stirred for 15 minutes. The addition of 30 ml of aqueous hydroxide solution 2N sodium was followed by dilution with 1 1 ethyl acetate and 200 ml water. The phases were separated and the organic phase was washed with 4 portions of 250 ml of 2N aqueous sodium hydroxide solution. The combined aqueous phases were extracted with 3 portions of 500 ml of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution and dried with sodium sulfate. The concentration gave 5.44 g of a brown-red oil. Flash column chromatography gave 2.15 g (41.3%) of the title compound as a light yellow solid. MS m / e (%): 260 (M +, 11). Melting point 91-93 ° C. c) N- (3,5-bis-trifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-tolyl-nicotinamide To a solution of 10.0 g (38.4 mmol) of 6-chloro-N-methyl- 4-O-tolyl-nicotinamide in 190 ml of tetrahydrofuran was added at 0 ° C 46 ml of a 1 M solution (46 mmol) of potassium hexamethyldisilazide in tetrahydrofuran. After 30 minutes, 8.5 ml (46 mmol) of 3,5-bis (trifluoromethyl) benzyl bromide was added dropwise to the resulting suspension. After the addition was complete, the ice-water cooling bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction was quenched with water. The mixture was adjusted to pH 3 with aqueous acid solution 1M hydrochloric acid and stirred for 10 minutes. Basification with 1 M aqueous sodium hydroxide solution to pH 8 was followed by concentration to remove the tetrahydrofuran. The aqueous residue was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated, which gave 21.4 g of crude product. Column chromatography gave 18.4 g (98.5%) of the title compound as a white solid. M? m / e (%): 485 ([M-H] +, 2) d) N- (3,5-bis-trifluoromethyl-benzyl) -N-methyl-4-o-tolyl-6- [1,2,4] triazol-1-yl-nicotinamide A mixture of 1.00 g (2.05 mmol) ) of N- (3,5-bis-trifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-tolyl-nicotinamide and 1.42 g (20.5 mmol) of 1,2,4-triazole was stirred at 130 ° C for 36 hours. After cooling to room temperature the crude mixture was purified by flash chromatography, which gave 0.93 g (87%) of the title compound as a white solid. MS m / e (%): 520 (M + H +, 100).

Example 2 N- (3,5-bis-trifluoromethyl-benzyl) -6- (2-hydroxy-ethylamino) -N-methyl-4-o-tolyl-nicotinamide A mixture of 0.837 g (1.72 mmol) of N- (3,5-bistrifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-tolyl-nicotinamide and 5.0 ml (83 mmol) of ethanolamine was stirred at 100 ° C. ° C for 48 hours. After cooling to room temperature the excess ethanolamine was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and water, dried with sodium sulfate and concentrated, which gave 0.8 g of crude product. Flash chromatography gave 0.650 g (73.9%) of the title compound as a white solid. MS m / e (%): 512 (M + H +, 100).

Example 3 (4, 5-bis-trifluoromethyl-benzyl) -methyl-amide of 4-hydroxy-4'-o-tolyl-3,4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl- 5'-carboxylic A mixture of 10.0 g (20.5 mmol) of N- (3, 5-bis-trifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-toli1-nicotinamide 3.1 g (31 mmol) of 4-hydroxypiperidine, 10.6 ml (62 mmol) of N-ethyldiisopropylamine and 0.13 g (1.0 mmol) of 4- (N, N-dimethylamino) -pyridine was stirred at 140 ° C for 70 hours.

After cooling to room temperature the residue was dissolved in a mixture of dichloromethane and water. The phases were separated and the aqueous phase was extracted with four portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated, which gave 11.1 g of crude product. Flash chromatography gave 9.0 g (80%) of the title compound as a white solid. MS m / e (%): 552 (M + H +, 100), Melting point 150-152 ° C.

Example 4 4- (2-hydroxy-ethoxy) -A '-o-tolyl-3,4,5,6-tetrahydro-2H- [3,5-bis-trifluoromethyl-benzyl] -methyl-amide , 2 '] bipyridinyl-5'-carboxylic acid a) 4- [2- (tert-Butyl-dimethyl-silanyloxy) -ethoxy] -4'-o-tolyl-3, 4,5 acid, (4,5-bis-trifluoromethyl-benzyl) -methyl-amide; 6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid A suspension of 48 mg (1.1 mmol) of sodium hydride (55% in oil) and 17 mg (0.045 mmol) of tetrabutylammonium iodide in 4.5 ml of dry tetrahydrofuran was added dropwise at 0 ° C, under argon, a solution of 0.50 g (0.91 mmol) of (3, 5-bis-trifluoromethyl-benzyl) -methyl-amide of 4- (2-hydroxy) ethoxy-4 '-o-tolyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-5'-carboxylic acid in 4.5 ml of dry tetrahydrofuran. After the addition was complete, it was allowed to warm to room temperature. After 1 hour 0.23 ml (1.1 mmol) of (2-bromoethoxy) -tert-butyl-dimethylsilane was added dropwise. The reaction mixture was heated to 50 ° C and stirred overnight. After cooling to room temperature, the reaction was quenched with the addition of 5 ml of water. The pH was adjusted to 2 with the addition of 1 M aqueous hydrochloric acid solution. After 5 minutes the mixture was basified with a saturated aqueous solution of sodium carbonate and extracted with 3 portions of ethyl acetate. The combined organic extracts were washed with water, dried with sodium sulfate and concentrated, which gave 0.79 g of a yellow oil. Flash chromatography gave 0.13 g (20%) of the title compound as a white solid. M? m / e (%): 710 (M + H +, 100). Initial material was recovered (0.21 g, 42%). b) 4- (2-hydroxy-ethoxy) -4'-o-tolyl-3,4,5,6-tetrahydro-2H- [3, 5-bis-trifluoromethyl-benzyl] -methyl-amide acid , 2 '] bipyridinyl-5'-carboxylic acid To a solution of 115 mg (0.162 mmol) of (4- [2- (tert-butyl-dimethyl-silanyloxy) (3,5-bistrifluoromethyl-benzyl) -methyl-amide ) -ethoxy] -4'-o-tolyl-3, 4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl-5'-carboxylic acid in 3 ml of Dry tetrahydrofuran was added 0.17 ml (0.17 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature under argon. After stirring overnight, the reaction mixture was diluted with ethyl acetate and washed with water. The phases were separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic extracts were washed with two portions of water, dried with magnesium sulfate and concentrated, which gave 111 mg of a yellow oil. Flash chromatography gave 59 mg (61%) of the title compound as a white solid. MS (m / e (%): 596 (M + H +, 100).

Example 5 (R) -N- (3,5-bis-trifluoromethyl-benzyl) -6- (3-hydroxy-pyrrolidin-1-yl) -N-methyl-4-o-tolyl-nicotinamide The compound of title in the form of a colorless amorphous mass with comparable yield according to the procedure described above for the preparation of 4-hydroxy-4'-o-tolyl-3 (3, 5-bistrifluoromethyl-benzyl) -methyl-amide, 4,5,6-tetrahydro-2H- [1,2 '] bipyridini1-5'-carboxylic acid. M? m / e (%): 538 (M + H, 100).

Example 6: 4 '(2-Chloro-phenyl) -4-hydroxy-3, 4,5,6-tetrahydro-2H- [1,2'] -6- (3, 5-bis-trifluoromethyl-benzyl) -methyl-amide ] bipyridinyl-5'-carboxylic a) 4-hydroxy-3,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid methylamide A mixture of 8.51 g (49.9 mmol) was refluxed overnight. of 6-chloro-N-methyl-nicotinamide, 5.66 g (54.9 mmol) of 4-hydroxypiperidine, 26.1 ml (150 ml) of N-ethyldiisopropylamine and 0.31 g (2.5 mmol) of 4- (N, N-dimethylamino) - pyridine. After cooling to room temperature the crude mixture was transferred to a flash chromatography column. Elution gave 10.1 g (86.1%) of the title compound as a light yellow solid. MS m / e 1%): 236 (M + H +, 100). b) 4- (tert-Butyl-dimethyl-silanyloxy) -3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid methylamide It was stirred at room temperature overnight mixture of 10.1 g (42.9 mmol) of 4-hydroxy-3, 5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid methylamide, 8.0 g (52 mmol) of tert-butyl dimethyl-chlorosilane and 6.5 g (94 mmol) of imidazole in 90 ml of N, N- dimethylformamide. The reaction was cooled with water. The resulting suspension was extracted with ethyl acetate. The organic extract was washed with 3 portions of water. The combined aqueous phases were extracted with 3 portions of dichloromethane. The combined organic extracts were dried with sodium sulfate, concentrated and dried under vacuum (0.5 mbar) at 80 ° C. Flash column chromatography gave 14.6 g (97.3%) of the title compound as a light yellow solid. MS m / e (%): 349 (M +, 21). c) 4- (tert-Butyl-dimethyl-silanyloxy) -4'-iodo-3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid methylamide To a solution of 500 mg (1.43 mmol) of 4- (tert-butyl-dimethyl-silanyloxy) -3,4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl-5'-carboxylic acid methylamide, 1.7 ml ( 11 mmol) of N, N, N ', N' -tetramethyl-ethylenediamine and 1.0 ml (5.7 mmol) of 2, 2, 6, 6-tetramethylpyridine in 9.5 ml of dry tetrahydrofuran 7.2 ml (11 mmol) of a 1.6 solution M of n-butyl lithium in hexanes was added dropwise, during 10 minutes, at -78 ° C under argon. The resulting solution was stirred at -78 ° C for 30 minutes, heated to -20 ° C and stirred at this temperature for 3 hours. After cooling of the reaction mixture to 78 ° C, it was added dropwise under Argon a solution of 2.92 g (11.5 mmol) of iodine in 7 ml of dry tetrahydrofuran. The resulting suspension was maintained at -78 ° C for 2 hours and then allowed to warm to room temperature for 1 hour. The suspension was poured into a solution of 12.4 g (50.0 mmol) of sodium thiosulfate pentahydrate in 50 ml of ice-water. The resulting yellow suspension was extracted with two 250 ml portions of tert-butyl methyl ether. The combined organic extracts were washed with 2 portions of a saturated aqueous ammonium chloride solution, dried with sodium sulfate and concentrated. Flash chromatography gave 495 mg (72.8%) of the title compound as a whitish amorphous mass. MS m / e (%): 476 (M + H +, 100). d) 4- (tert-Butyl-dimethyl-silanyloxy) -4'- (2-chloro-phenyl) -3,4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl-5' methylamide -carboxylic A mixture of 480 mg (1.01 mmol) of 4- (tert-butyl-dimethyl-silanyloxy) -amino-3, 5,6-tetrahydro-2H- [1,2 '] bipyridinyl methylamide -5'-carboxylic acid, 174 mg (1.11 mmol) of 2-chlorophenylboronic acid, 6 ml of dimethoxyethane and 1 ml of a 2 M aqueous solution of sodium carbonate are deoxygenated by freeze-thaw cycles. After the addition of 60 mg (0.052 mmol) of tetrakis (triphenylphosphine) palladium (O), the mixture of reaction at 90 ° C for 3 hours. Cooling to room temperature was followed by dilution with water and extraction with ethyl acetate. The organic extract was washed with solutions of sodium carbonate and saturated aqueous sodium chloride, dried with sodium sulfate and concentrated. Column chromatography gave 425 mg (91.5%) of the title compound as a whitish solid. MS m / e (%): 460 (M + H +, 100). e) 4- (tert-butyl-dimethyl-silanyloxy) - '- (2-chloro-phenyl) -3,4,5,6-tetrahydro (3,5-bis-trifluoromethyl-benzyl) -methyl-amide -2H- [1,2 '] bipyridinyl-5'-carboxylic acid The title compound was obtained as a whitish foam in 49% yield according to the procedure described above for the preparation of N- (3, 5- bis-trifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-tolyl-nicotinamide using 4- (tert-butyl-dimethyl-silanyloxy) -4 '- (2-chloro-phenyl) -3-methylamide , 4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxy instead of 6-chloro-N-methyl-4-o-tolyl-nicotinamide. M? m / e (%): 685 (M +, 40). f) (3, 5-bis-trifluoromethyl-benzyl) -methyl-amide of 4 '- (2-chloro-phenyl) -4-hydroxy-3,4,5,6-tetrahydro-2H- (1,2 '] bipyridinyl-5'-carboxylic acid The title compound was obtained as a white solid in 82% yield in accordance with the procedure described above for the preparation of (34- (2-hydroxy-ethoxy) -4'-o-tolyl-3,4,5,6-tetrahydro-2H- [1, 2 '], 5-bis-trifluoromethyl-benzyl) -methyl-amide bipyridinyl-5'-carboxylic acid using (3,5-bis-trifluoromethyl-benzyl) -methylamide of 4- (tert-butyl-dimethyl-silanyloxy) -A '- (2-chloro-phenyl) -3,4,5 , 6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxy in place of 4- [2- (tert-butyl-dimethyl) (3,5-bis-trifluoromethyl-benzyl) -methyl-amide] -silyloxy) -ethoxy] -A '-o-tolyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-5'-carboxylic acid. MS m / e (%): 572 (M + H +, 100).

Example 7 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2-hydroxy-ethylamino) -4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide To one solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 150 ml of tetrahydrofuran was added dropwise to 27 ml (315 mmol) of morpholine within 10 minutes. The reaction mixture was refluxed for a further 2 hours. After cooling to room temperature the solvent was removed in vacuo and the residue redissolved in 200 ml of ethyl acetate. The organic phase was washed with 200 ml of IN sodium bicarbonate solution, dried (magnesium sulfate) and evaporated, which gave 27.3 g (quantitative) of the title compound in the form of a yellow solid. Melting point 142-143 ° C. b) 2, 2-dimethyl-N- (6-morpholin-4-yl-pyridin-3-yl) -propionamide To a solution of 27.3 g (126 mmol) of 4- (5-nitro-2-pyridyl) - morpholine in 600 ml of methanol was added 2.5 g of 10% palladium on activated charcoal. The reaction mixture was hydrogenated (room temperature to about 45 ° C, 1.0197 kg / cm 2 (1 bar)) until the theoretical amount of hydrogen was collected (about 3 hours). The catalyst was filtered off and washed twice with 100 ml portions of methanol. The filtrate was evaporated in vacuo, which gave 22.6 g of a purple oil which was constituted by about 95% of the desired aniline derivative according to analysis by thin layer chromatography. This crude product was dissolved in a mixture of 240 ml of tetrahydrofuran and 60 ml of diethyl ether. After cooling to 0 ° C, 26 ml (189 mmol) of triethylamine was added in one portion. Agitation was continued while 23 g (189 mmol) of pivaloyl chloride were added dropwise within a period of 10 minutes. The ice bath was removed and the reaction mixture was stirred for 1 hour at room temperature. Then the solvent was removed in vacuo and the residue was suspended in 200 ml of sodium bicarbonate solution IN. The product was extracted three times with 200 ml portions of dichloromethane, dried (sodium sulfate) and evaporated. Recrystallization of the solid residue in ethyl acetate / hexane 1: 8 gave 28.6 g (86%) of the title compound as white crystals. M? m / e (E): 264 (M + H +, 100). c) N- (4-iodo-6-morpholin-4-yl-pyridin-3-yl) -2, 2-dimethyl-propionamide A solution of 28.4 g (108 mmol) of 2,2-dimethyl-N- ( 6-morpholin-4-yl-pyridin-3-yl) -propionamide and 49 ml (324 mmol) of N, N ', N' -tetramethylethylenediamine under argon in 600 ml of tetrahydrofuran was cooled in an ice bath until -78 ° C. Within 1 hour 202 ml (324 mmol) of a solution of n-butyllithium 1.6 N in hexane was added dropwise. The reaction mixture was allowed to warm to -35 ° C overnight. After cooling again to -78 ° C, 37 g (146 mmol) of iodine dissolved in 60 ml of tetrahydrofuran was added dropwise over 15 minutes. The dry ice bath was replaced by an ice bath and a solution of 90 g (363 mmol) of sodium thiosulfate pentahydrate in 250 ml of water was added within 10 minutes when the temperature of the reaction mixture had reached 0 °. C. Then 1000 ml of diethyl ether were added and the organic phase was separated. The aqueous phase was extracted twice with 500 ml of dichloromethane and the combined organic phases were dried (magnesium sulfate) and evaporated. Flash chromatography gave 15.6 g (37%) of the title compound as a light brown oil which crystallized after standing at room temperature.

MS m / e (%): 389 (M +, 71), 358 (25), 304 (43), 57 (100). d) 2, 2-dimethyl-N- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -propionamide A mixture of 3.50 g (9.0 mmol) of N- (4-iodo- 6-morpholin-4-yl-pyridin-3-yl) -2,2-dimethyl-propionamide, 35 ml of toluene, 18 ml of 2N sodium carbonate solution, 312 mg (0.27 mmol) of tetrakis (triphenylphosphine) palladium (O) and 1.34 g (9.9 mmol) of o-tolylboronic acid was heated under argon at 80 ° C for 12 hours. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic phases were washed with 50 ml of brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography gave 3.23 g (quantitative) of the title compound as a white foam. MS m / e (%): 354 (M + H +, 100). e) 6-morpholin-4-yl-4-o-tolyl-pyridin-3-ylamine A suspension of 2.93 g (8.28 mmol) of 2,2-dimethyl-N- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -propionamide in 80 ml of hydrochloric acid solution 3 N and 5 ml of 1-propanol was heated to 90-95 ° C overnight. The reaction mixture was cooled to room temperature, washed with three 20 ml portions of diethyl ether and filtered over celite. The filtrate was diluted with 20 ml of water and adjusted to pH 7-8 with the addition of 28% sodium hydroxide solution under ice-cooling. The product was extracted with four 100 ml portions of dichloromethane. The combined organic phases were washed with 50 ml of brine, dried (magnesium sulfate) and evaporated, which gave 2.31 g (quantitative) of the title compound as a white foam. MS m / e (%): 269 (M +, 100). f) Methyl- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -amine A solution of 2.24 g (8.3 mmol) of 6-morpholin-4-yl-4-o-tolyl -pyridin-3-ylamine in 17 ml of trimethyl-ortho- formate and 3 drops of trifluoroacetic acid was heated for 2 hours at 130 ° C. The reaction mixture was evaporated and dried under vacuum for 30 minutes. The residual oil was dissolved in 5 ml of tetrahydrofuran and added dropwise under ice cooling to 630 mg (16.6 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran. The reaction mixture for 1 hour at room temperature, cooled to 0 ° C again and acidified (pH 1-2) by addition of 28% hydrochloric acid solution. After stirring for 5 minutes, 28% sodium hydroxide solution was added to reach pH 10. The solution was filtered over celite, evaporated and purified by flash chromatography, which gave 1.56 g (66%) of the title compound as of a white foam. MS m / e (%): 283 (M +, 100). g) 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-N- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -isobutyramide A solution of 1.46 g (5.15 mmol) of methyl- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -amine and 1.32 ml (7.73 mmol) of N-ethyldiisopropylamine in 15 ml of dichloromethane was cooled in a ice bath and 1.8 g (5.67 mmol) of 2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl chloride was added dropwise. The reaction mixture was heated to 35-40 ° C for 3 hours, cooled to room temperature again and stirred with 25 ml of saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 2.9 g (quantitative) of the title compound as crystals whites. Melting point 131-132 ° C. h) 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2-hydroxy-ethylamino) -4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide A mixture of 1.0 g (1.76 mmol) of 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-N- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl) -isobutyramide , 100 mg (0.48 mmol) of ruthenium chloride (III) hydrate, 832 mg (3.87 mmol) of sodium periodate, 3.5 ml of carbon tetrachloride, 3.5 ml of ecetonitrile and 5.3 ml of water were stirred for 4 days at room temperature . Dichloromethane was added, the organic phase was separated, washed with sodium hydrogensulfite solution and filtered over celite. To the filtrate, 10 ml of IN potassium hydroxide solution and 20 ml of methanol were added. After heating the mixture for 1 hour at 40 ° C, the solvents were removed in vacuo and the residue was purified by flash chromatography, which gave 352 mg (37%) of the title compound, as a light brown foam. MS m / e (%): 540 (M + H +, 100).

EXAMPLE 8 2- (3,5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethylamino) -pyridin-3-yl] -N-methyl- isobutyramide The title compound was obtained in the form of a light brown foam with comparable performance in accordance with the procedures described above for the preparation of 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2-hydroxy-ethylamino) -4-o-tolyl- pyridin-3-yl] -N-methyl-isobutyramide using 2-chloroboronic acid instead of o-tolylboronic acid in step d). M? m / e (%): 560 (M + H +, 100).

Example 9 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (2,3-dihydro- [1,4] oxazin-4-yl) -4-o-tolyl-pyridin-3- il] -N-methyl-isobutyramide a) 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-N- [6- (3-oxo-morpholin-4-yl) -4-o-tolyl-pyridin-3-yl] - Isobutyramide To an ice-cooled suspension of 1.2 g (7.1 mmol) of ruthenium oxide (IV) hydrate in a mixture of 50 ml of carbon tetrachloride and 50 ml of water was added 9.0 g. (42 mmol) of sodium periodate. After stirring for 30 minutes, the organic phase was separated and the aqueous phase was extracted twice with 10 ml portions of carbon tetrachloride. The combined organic phases were filtered over celite, cooled to 0 ° C and slowly added to an ice-cooled solution of 2.0 g (3.54 mmol) of 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl. -N- (6-morpholin-4-yl-4-o- tolyl-pyridin-3-yl) -isobutyramide in 20 ml of carbon tetrachloride. The mixture was stirred for an additional 15 minutes at 0 ° C, filtered over celite and evaporated. The residue was purified by flash chromatography and gave 704 mg (34%) of the title compound as a colorless foam. MS m / e (%): 580 (M + H +, 100). b) (RS) -2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (3-hydroxy-morpholin-4-yl) -4-o-tolyl-pyridin-3-yl] - N-methyl-isobutyramide To an ice-cooled solution of 494 mg (0.852 mmol) of 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-N- [6- (3-oxo-morpholin-4) -yl) -4-o-tolyl-pyridin-3-yl] -isobutyramide in 5 ml of methanol and 5 ml of tetrahydrofuran was added 635 mg (1.70 mmol) of cerium (III) chloride heptahydrate. After stirring for 5 minutes, 64 mg (1.70 mmol) of sodium borohydride was added in two portions within 2 minutes. After stirring for 3 hours at 0 ° C, 1 ml of acetone was added and stirring was continued for 10 minutes. The solvent was removed, the residue was redissolved in ethyl acetate and the organic phase was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The crude material was purified by flash chromatography, which gave 87 mg (16%) of the title compound as white crystals. MS m / e (%): 582 (M + H +, 100). c) 2- (3, 5-bis-trifluoromethyl-phenyl) -N- [6- (2,3-dihydro- [1,4] oxazin-4-yl) -4-o-tolyl-pyridin-3- il] -N-methyl-isobutyramide To a solution of 65 mg (0.11 mmol) of (RS) -2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (3-hydroxy-morpholin-4) -yl) -4-o-tolyl-pyridin-3-yl] -N-methyl-isobutyramide in 2 ml of chloroform were added a few drops of a 2.3 N hydrochloric acid solution in diethyl ether. After stirring at room temperature for 2 hours, the organic phase was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The residue was purified by flash chromatography, which gave 47 mg (75%) of the title compound as a white foam. M? m / e (%): 564 (M + H +, 100).

EXAMPLE 10 N- (6-Acetylamino-4-o-tolyl-pyridin-3-yl) -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide a) N 2 -benzyl-N 5 -methyl -4-o-tolyl-pyridin-2, 5-diamine The title compound was prepared following the procedures described above for the synthesis of methyl- (6-morpholin-4-yl-4-o-tolyl-pyridin-3-) il) -amine. MS m / e (%): 304 (M + H +, 100). b) benzyl- (5-methylamino-4-o-tolyl-? iridin-2-yl) -carbamic acid benzyl ester To a solution of 2.03 g (6.7 mmol) of N2-benzyl-N5-methyl-4-o tolyl-pyridine-2, 5-diamine in 100 ml of dichloromethane and 40 ml of N-ethyldiisopropylamine was added dropwise at 0 ° C a solution of 2.1 ml (14.09 mmol) of benzyl chloroformate in 50 ml of dichloromethane. After stirring for 2 hours at room temperature, the reaction mixture was washed with water (2 x 50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue gave 2.36 g (80%) of the title compound as clear brown crystals. Melting point 110-112 ° C. MS m / e (%): 438 (M + H +, 100). c) Benzyl- (5- {[2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin benzyl ester -2-yl) -carbamic acid To a solution of 1075 g (2.5 mmol) benzyl- (5-methylamino-4-o-tolyl-β-iridin-2-yl) -carbamic acid benzyl ester in 10 ml of dichloromethane and 1 ml of N-ethyldiisopropylamide was added dropwise at 0 ° C a solution of 1.15 g (3.5 mmol) of 2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionic acid chloride in 2 ml of dichloromethane and the mixture was stirred for 3 hours at room temperature. The solution was washed with water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and brine (20 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue gave 1.15 g (62%) of the title compound as a yellow oil. M? m / e (%): 720 (M + H +, 100). d) N- (6-benzylamino-4-o-tolyl-pyridin-3-yl) -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide To a solution of 973 mg (1.35 mmol ) benzyl- (5- {[2- (3,5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin benzyl ester -2-yl) -carbamic acid in 13 ml of methanol and 1 ml of N, N-dimethylformamide were added 40 mg of palladium on 10% activated carbon and the mixture was hydrogenated (room temperature, 1.0197 kg / cm2 (1 bar) ) for 1 hour. Filtration of the catalyst and evaporation of the filtrate gave 795 mg (quantitative) of the title compound as a yellow oil. MS m / e (%): 586 (M + H +, 100). e) N- (6-amino-4-o-tolyl-pyridin-3-yl) -2- (3, 5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide A solution of 750 mg (1.28 mmol) of N- (6-benzylamino-4-o-tolyl-pyridin-3-yl) -2- (3, 5-bis- trifluoromethyl-phenyl) -N-methyl-isobutyramide in 25 ml of a 5 N solution of hydrochloric acid in ethanol was evaporated to dryness and the residue was dissolved in 30 ml of methanol and hydrogenated in the presence of 60 mg of palladium on activated carbon at 10% (room temperature, 10,197 kg / cm2 (10 bar)) for 20 hours. After filtration of the catalyst and evaporation of the solvent, the residue was dissolved in 30 ml of ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution gave 514 mg (81%) of the title compound as clear brown crystals. MS m / e (%): 496 (M + H +, 100). f) N- (6-acetylamino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide To a solution of 100 mg (0.20 mmol ) of N- (6-amino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide in 3 ml of dichloromethane was added 27 mg (0.21 mmol) of N-ethyldiisopropylamine and 70 mg (0.69 mmol) of acetic anhydride. After stirring overnight, the solvent was evaporated and the residue was purified by flash chromatography, which gave 100 mg (92%) of the title compound as a white solid. MS m / e (%): 537 (M +, 68), 282 (100).

EXAMPLE 11 N- [6- (Acetyl-methyl-amino) -4-o-tolyl-pyridin-3-yl] -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide To one solution 60 mg (0.11 mmol) of N- (6-acetylamino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide in 2 ml of tetrahydrofuran at room temperature under argon was added dropwise 0.13 ml (0.12 mmol) of a 1M solution of potassium hexamethyldisilazide in tetrahydrofuran. Stirring was continued for 1 hour at room temperature and 17 mg (0.12 mmol) of methyl iodide was added. After stirring overnight the solvent was evaporated and the residue was purified by flash chromatography, which gave 40 mg (65%) of the title compound as a white foam. MS m / e (%): 574 (M + Na +, 17), 552 (M + H +, 100).

Example 12 (5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin-2-yl) - cyclopropanecarboxylic acid amide To a solution of 100 mg (0.20 mmol) of N- (6-amino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N -methyl-isobutyramide in 3 ml of dichloromethane were added 2 ml of pyridine and 23 mg (0.22 mmol) of acid chloride cyclopropancarboxylic acid at 0 ° C. After stirring for 2 days at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography, which gave 61 mg (54%) of the title compound as a white solid. MS m / e (%): 586 (M + Na +, 25), 564 (M + H +, 100).

Example 13 (5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin-2-yl) - Methyl-amide of cyclopropanecarboxylic acid. The title compound was prepared in the form of a white foam with comparable yield according to the procedure described above for the preparation of N- [6 (acetyl-methyl-amino) -4-o-tolyl-pyridin-3-yl] -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide using (5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4- or -tolyl-pyridin-2-yl) -amide cyclopropanecarboxylic acid in place of N- (6-acetylamino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide. MS m / e (%): 600 (M + Na +, 22), 578 (M + H +, 100).

Example 14 2- (3,5-bis-trifluoromethyl-phenyl) -N- (6-imidazol-1-yl-4-o- tolyl-pyridin-3-yl) -N-methyl isobutyramide a) 6-imidazol-l-yl-4-o-tolyl-pyridin-3-ylamine The title compound was obtained as a light brown foam in accordance with the procedures described above for the preparation of 6-morpholin-4 -yl-4-o-tolyl-pyridin-3-ylamine (Example 7, step e)) using imidazole in place of morpholine in step a). MS m / e (%): 251 (M + H +, 100). b) 2- (3,5-bis-trifluoromethyl-phenyl) -N- (6-imidazol-1-yl-4-o-tolyl-pyridin-3-yl) -isobutyramide The title compound was obtained in the form of yellow crystals according to the procedure described above for the preparation of 2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-N- (6-morpholin-4-yl-4-o-tolyl-pyridine- 3-yl) -isobutyramide (Example 7, step g)) using 6-imidazol-l-yl-4-o-tolyl-pyridin-3-ylamine instead of methyl- (6-morpholin-4-yl-4-) o-tolyl-pyridin-3-yl) -amine. M? m / e (%): 532 (M +, 100). c) 2- (3,5-bis-trifluoromethyl-phenyl) -N- (6-imidazol-1-yl-4-o-tolyl-pyridin-3-yl) -N-methyl-isobutyramide The compound of Title in the form of white crystals in accordance with the procedure described above for the preparation of N- (3,5-bis-trifluoromethyl-benzyl) -6-chloro-N-methyl-4-o-tolyl-nicotinamide (Example 1, step c)) using 2- (3, 5 -bis-trifluoromethyl-phenyl) -N- (6-imidazol-l-yl-4-o-tolyl-pyridin-3-yl) -isobutyramide instead of 6-chloro-N-methyl-4-o-tolyl- nicotinamide and methyl iodide instead of 3,5-bis (trifluoromethyl) benzyl bromide. MS m / e (%): 547 (M + H +, 100).

EXAMPLE A In the usual way, tablets of the following composition were prepared: mg / tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate 1 Weight per tablet 100 Example B Capsules of the following composition are prepared: Mg / capsule Active substance 10 Lactose 155 Corn starch 30 Talcum 5 Weight of capsule filling 200 The active substance, lactose and corn starch are first mixed in a mixer, and then in a crushing machine. The mixture is returned to the mixer, the talc is added and mixed thoroughly. The mixture is machine-filled in hard gelatin capsules.

Example C Suppositories of the following composition are prepared: mg / suppository Active substance 15 Suppository mass 1285 Total 1300 The suppository mass is melted in a glass or steel container, mixed thoroughly and cooled to 45 ° C. Then the finally pulverized active substance is added and stirred until it has completely dispersed. Pour the mixture into suppository molds of appropriate size, let it cool, then remove the suppositories of the molds and are individually packaged in wax paper or metal foil.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the general formulas characterized because R1 is or is -NH (CH2) 2OH, -NRJC (0) CH3 or -NR3C (0) -cyclopropyl; R2 is methyl or chloro; R3 is hydrogen or methyl; R is hydrogen or - (CH 2) 2 OH; and n is 1 or 2 and its pharmaceutically acceptable acid addition salts 2. A compound of formula IA in accordance with

Claim 1, characterized in that R2 is methyl. 3. A compound according to claim 2, characterized in that it is N- (3,5-bis-trifluoromethyl-benzyl) -N-methyl-4-o-tolyl-6- [1,2,4] triazole-1. -yl-nicotinamide, N- (3,5-bis-trifluoromethyl-benzyl) -6- (2-hydroxy-ethylamino) -N-methyl-4-o-tolyl-nicotinamide, (3, 5-bis-trifluoromethyl- benzyl) -methyl-amide of 4-hydroxy-4 '-o-tolyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyridini-5'-carboxylic acid, (3,5-bis- 4- (2-hydroxy-ethoxy) -4 '-o-tolyl-3,4,5,6-tetrahydro-2H- [1,2'] bipyridinyl-5 '- trifluoromethyl-benzyl) -methyl-amide carboxylic or (R) -N- (3,5-bis-trifluoromethyl-benzyl) -6- (3-hydroxy-pyrrolidin-1-yl) -N-methyl-4-o-tolyl-nicotinamide. 4. A compound of formula IA according to claim 1, characterized in that R2 is chlorine. 5. A compound according to claim 4, characterized in that it is (3, 5-bis-trifluoromethyl-benzyl) -methyl-amide of 4 '- (2-chloro-phenyl) -4-hydroxy-3, 5 , 6-tetrahydro-2H- [1,2 '] bipyridinyl-5'-carboxylic acid. 6. A compound of formula IB according to claim 1, characterized in that R2 is methyl. 7. A compound according to claim 6, characterized in that it is 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2-hydroxy-ethylamino) -4-o-tolyl-pyridin-3-yl. ] -N-methyl-isobutyramide, 2- (3,5-bis-trifluoromethyl-phenyl) -N- [6- (2,3-dihydro- [1,4] oxazin-4-yl) -4-o- tolyl-pyridin-3-yl] -N-methyl-isobutyramide, N- (6-acetylamino-4-o-tolyl-pyridin-3-yl) -2- (3,5-bis-trifluoromethyl-phenyl) -N -methyl-isobutyramide, N- [6- (acetyl-methyl-amino) -4-o-tolyl-pyridin-3-yl] -2- (3,5-bis-trifluoromethyl-phenyl) -N-methyl-isobutyramide (5- {[2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin-2-yl) -amide of cyclopropanecarboxylic acid, (5- { [2- (3, 5-bis-trifluoromethyl-phenyl) -2-methyl-propionyl] -methyl-amino} -4-o-tolyl-pyridin-2-yl ) -methyl-amide of cyclopropanecarboxylic acid or 2- (3,5-bis-trifluoromethyl-phenyl) -N- (6-imidazol-l-yl-4-o-tolyl-pyridin-3-yl) -N-methyl -isobutyramide. 8. A compound of formula IB according to claim 1, characterized in that R2 is chlorine. 9. A compound according to claim 8, characterized in that it is 2- (3,5-bis-trifluoromethyl-phenyl) -N- [4- (2-chloro-phenyl) -6- (2-hydroxy-ethylamino) ) -pyridin-3-yl] -N-methyl- isobutyramide 10. A medicament, characterized in that it contains one or more compounds according to any of claims 1-9 and pharmaceutically acceptable excipients. 11. A medicament according to claim 10, characterized in that it is for the treatment of diseases related to NK-1 receptor antagonists. 12. A process for the preparation of a compound of formula I according to claim 1, the method is characterized in that it comprises a) reacting a compound of formula with a compound of formula to a compound of the formula wherein R1 and R2 have the meaning indicated in claim 1, or b) reacting a compound of formula with a compound of formula V to give a compound of formula where R1 and Rz have the meaning indicated in the claim 1, or c) reacting a compound of formula with a compound of formula to a compound of formula wherein Z is Cl, Br, I, -OS (0) 2CeHiCH3 or -O (0) 2CH3 and the other definitions of the substituents have been given in claim 1, reacting a compound of formula with a compound of formula RSH XIV to a compound of the formulas wherein the definition of substituents has been given in claim 1, and if desired, converting the obtained compound to a pharmaceutically acceptable acid addition salt. 13. A compound according to any of claims 1-9, characterized in that it is prepared with a process according to claim 12, or with an equivalent method. 14. The use of a compound in accordance with any of claims 1-9 for the treatment of diseases related to NK-1 receptor antagonists. 15. The use of a compound according to any of claims 1-9 for the preparation of medicaments containing one or more compounds of formula I for the treatment of diseases related to NK-1 receptor antagonists.